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ABSTRACTThe Stellarex® drug-coated balloon (DCB) is an over-the-wire dual lumen catheter with a distally premounted semi-compliant balloon, which has a low dose (2 μg/mm2of the expanded balloon surface) paclitaxel coating. Its hybrid formulation, made of amorphous and crystalline paclitaxel combined with a polyethylene glycol excipient, provides maintenance of coating integrity and adequate drug release. This balanced combination of amorphous and crystalline paclitaxel is able to maintain drug on the surface during handling and balloon tracking, with an effective drug transfer to vessel wall in the lesion site. Clinical data associated with Stellarex balloon are growing and confirm clinical effectiveness over a long-term follow-up without any possible signal of a reduced safety for treated patients.

The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme.

Aim Chronic ischaemic cardiovascular disease (CICD) remains a leading cause of morbidity and mortality worldwide. The CICD Pilot Registry enrolled 2420 patients across 10 European Society of Cardiology countries prospectively to describe characteristics, management strategies and clinical outcomes in this setting. We report here the six-month outcomes.Methods and results From the overall population, 2203 patients were analysed at six months. Fifty-eight patients (2.6%) died after inclusion; 522 patients (23.7%) experienced all-cause hospitalisation or death. The rate of prescription of angiotensin-converting enzyme inhibitors, beta-blockers and aspirin was mildly decreased at six months (all P< 0.02). Patients who experienced all-cause hospitalisation or death were older, more often had a history of non-ST-segment elevation myocardial infarction, of chronic kidney disease, peripheral revascularisation and/or chronic obstructive pulmonary disease than those without events. Independent predictors of all-cause mortality/hospitalisation were age (hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07–1.27) per 10 years, and a history of previous peripheral revascularisation (HR 1.45, 95% CI 1.03–2.03), chronic kidney disease (HR 1.31, 95% CI 1.0–1.68) or chronic obstructive pulmonary disease (HR 1.42, 95% CI 1.06–1.91, all P< 0.05). We observed a higher rate of events in eastern, western and northern countries compared to southern countries and in cohort 1.Conclusion In this contemporary European registry of CICD patients, the rate of severe clinical outcomes at six months was high and was influenced by age, heart rate and comorbidities. The medical management of this condition remains suboptimal, emphasising the need for larger registries with long-term follow-up. Ad-hoc programmes aimed at implementing guidelines adherence and follow-up procedures are necessary, in order to improve quality of care and patient outcomes.

Since the first human catheterization performed by Forssman in 1929 angioplasty equipment and medical therapies have undergone considerable evolution and technical improvement allowing interventionalists to perform more complex procedures and solving most of the percutaneous limitations. While percutaneous coronary intervention (PCI) has dramatically changed the outcome in the Acute Coronary Syndrome (ACS) setting, its role in the treatment of chronic stable angina is still debated. Stable coronary artery disease (SCAD) is a major public health issue and its prevalence is still increasing in the industrialized world. The correct treatment sees a multi-strategy approach aimed to a relief of symptoms, prevention of future cardiac events and survival improvement. In so forth, treatment strategies include optimal medical therapy (OMT) alone or combined with percutaneous or surgical coronary revascularization. Despite this, angina remains poorly controlled in the vast majority of CAD patients. Traditional agents such Beta-blockers or Calcium channel blockers or short and long acting nitrates have been used as first-line anti-anginal therapy for several years. Nowadays newer and more effective drugs usually used on top of older medical treatment have become available.

Carotid artery stenting is a rapidly evolving method for treating carotid artery disease. Various intraprocedural and postprocedural complications have been reported in the literature. However, the absence of a unified classification scheme for these complications makes it difficult, if not impossible, to study their precise incidence, predictors, and management. The aim of this article is to propose the first joint classification of periprocedural complications, to analyze their incidence and etiology, and suggest possible ways to manage and prevent them. This classification is intended to be used as a common platform for prompt recognition, evaluation, treatment, and universal study of the complications during carotid stenting procedures. For this purpose, the opinions of the major experts on carotid interventions worldwide were merged with all the available information reported in the English-language literature to present as accurately as possible the management and prevention of carotid stenting complications according to this proposed classification.

Purpose: To report a prospective feasibility study of Cutting Balloon angioplasty (CBA) applied in the predilation phase of carotid artery stenting (CAS) in highly calcified lesions.Methods: From January 2003 to February 2007, 178 consecutive patients (109 men; mean age 73.1±7.3 years) with highly calcified carotid lesions underwent CAS with CBA applied as a pre-specified strategy in the predilation phase of the procedure. All steps in the procedure were performed under cerebral filter protection. The cutting balloon ranged in diameter from 3 to 4 mm and was inflated at nominal pressures in the target lesion. Pre-CBA dilation with a low-profile coronary balloon was performed only when the Cutting Balloon was not able to cross the lesion. Selection of the filters and stents was at the operator's discretion. Primary endpoints were the all stroke and death rates at 30 days and 6 months. Secondary endpoints included Cutting Balloon success (positioning and full balloon inflation), CAS technical success (residual angiographic stenosis <30%), CAS procedural success (technical success and no complications), and in-hospital major complications.Results: Cutting Balloon success was achieved in all 178 patients. In 32 (18.0%), pre-CBA dilation was necessary due to inability to cross the lesion with the Cutting Balloon initially. CAS technical success was achieved in all patients. One (0.6%) patient suffered transient neurological intolerance due to flow cessation from massive debris in the distal filter; this event was completely resolved after the filter was removed (CAS procedural success 99.4%). One patient suffered a major stroke at day 15 (0.6% 30-day all stroke and death rate). At the 6-month follow-up, 174 (97.7%) patients were evaluated; 1 patient died from myocardial infarction at day 35, and 2 patients died from non-neurological or cardiac causes at days 103 and 158. The cumulative all stroke and death rate was 2.2%.Conclusion: These data suggest that CBA performed during the predilation phase of CAS in highly calcified lesion is a safe and useful method to prepare this lesion subset for stenting.

Purpose: To report the results from a prospective multicenter registry evaluating the safety and performance of a new hybrid stent specifically engineered for carotid indications.Methods: Between October 18, 2006, and March 28, 2007, 124 patients (88 men; mean age 71.8±7.3 years, range 52–87) underwent Cristallo Ideale stent implantation at 4 expert sites in Italy and Germany. Eligibility criteria included >60% symptomatic and >80% asymptomatic carotid stenosis. Different cerebral protection devices were utilized (proximal protection and distal filters). The primary endpoint was the rate of 30-day major adverse neurological events, defined as major and minor stroke and neurological death by independent neurological assessment. All adverse events were adjudicated by an independent clinical event committee.Results: Stent deployment was completed successfully in all the cases without documented technical failure. There were no neurological events during the procedures. Thirty-day follow-up was available for 119 (96.0%) patients [2 (1.6%) were lost to follow-up and 3 (2.4%) died from non-neurological causes unrelated to the device or procedure]. There were no major adverse neurological events within 30 days, but 2 (1.6%) device-/procedure-related transient ischemic attacks were reported (both resolved completely in <24 hours). Four (3.2%) other non-neurological events (anemia requiring transfusion, worsening of pre-existing chronic renal failure, acute access site thrombosis, and monocular vision disturbance) were reported in the study period.Conclusion: The Cristallo Ideale carotid stent is safe and effective in the periprocedural period. Its newly designed hybrid structure seems to support the rationale of combining adequate plaque scaffolding with high vessel adaptability.

Purpose: To assess the impact of diabetes, patient age, and gender on major periprocedural (30-day) complications (major and minor strokes, all-cause deaths) following carotid artery stenting (CAS).Methods: An exploratory analysis was performed of 695 patients (516 men; mean age 69.9±8.4 years) enrolled consecutively between September 1999 and September 2002 in a multicenter Italian/German registry of routine CAS using cerebral protection devices. There were 535 nondiabetic patients and 160 diabetic patients in the analysis.Results: Logistic regression analysis revealed that diabetes and age, but not gender, impacted the cumulative 30-day incidence of any stroke and death (OR 2.1, 95% CI 1.0 to 4.8, p=0.068 and OR 1.06, 95% CI 1.01 to 1.12, p=0.031, respectively), as well as the 30-day incidence of major strokes and deaths (OR 5.9, 95% CI 1.6 to 21.8, p=0.007 and OR 1.13, 95% CI 1.02 to 1.25, p=0.018, respectively). According to receiver-operating characteristic analysis, age had no discriminatory power to predict complications in nondiabetic patients, but an age of 75 years was identified as the optimal cut point to predict complications in diabetic patients. Compared with nondiabetic patients, diabetics ≥75 years had a 4.3 greater risk of experiencing any stroke or death (95% CI 1.3 to 12.3, p=0.016) and a 12.0 greater risk of a major stroke or death (95% CI 2.1 to 66.5, p=0.005). Diabetics < 75 years had no increase in risk over that of nondiabetic patients.Conclusion: Diabetic patients ≤75 years carry a significantly increased risk for strokes or death after protected CAS. The findings should be taken into consideration when treating elderly diabetic patients.

The prevention of stroke and the correct treatment of carotid artery stenosis represent today a major debate in cardiovascular medicine. Beside carotid endarterectomy, carotid angioplasty and stenting is becoming more widely performed for the treatment of severe carotid obstructive disease, and is now accepted as a less invasive technique that may provide an alternative for selected patients, particularly those with significant comorbidities. An Italian multidisciplinary task force, in which converged the most representative scientific societies involved in carotid treatment, was created to provide neurologists, radiologist, cardiologists, vascular surgeons, and all those involved in prevention and treatment of carotid disease with a simple, clear and updated evidence-based consensus document.

Purpose: To evaluate (1) whether carotid artery stenting (CAS) performed in octogenarians increases the procedure-related risk and (2) the incidence of complex anatomy of the aortic arch and supra-aortic vessels in patients >80 years old, which can increase the technical difficulty of CAS.Methods: Between December 2000 and September 2005, 1053 patients (903 men; mean age 72±2.2 years, range 46–90) underwent 1222 CAS procedures in 2 centers for de novo (n=1192) and restenotic (n=30) lesions (139 staged bilateral procedures). Indications for treatment were the presence of a symptomatic carotid artery stenosis ≥70% (n=798, 65.3%) or an asymptomatic stenosis of at least 80%. The patients were separated into 2 age categories: under 80 (n=1078 procedures, 88.2%) and 80 or older (n=144 procedures, 11.8%) for this analysis. Data analysis included death and stroke rate at discharge and at 30 days. Anatomical characteristics evaluated were aortic arch elongation, arch and supra-aortic vessel calcification and tortuosity, anatomical tortuosity of the lesion, and carotid plaque composition.Results: Three lesions in octogenarians could not be treated because of failure to access the vessel in 1 case and extremely tortuous arteries in 2. The overall death and stroke rate at 30 days was 2.12% in the older group (2 fatal strokes, 1 minor stroke) and 1.11% in the younger group (3 deaths, 3 major strokes, 6 minor strokes); the difference was not statistically significant (p=0.40). Significantly higher frequencies of tortuosity and calcification of the arch and supra-aortic vessels and of type III aortic arch were observed in the older group (p<0.001).Conclusion: In our experience, CAS has proven to be safe and effective in elderly patients. Different age-related anatomical features can represent an adjunctive technical challenge, but these difficulties can be successfully managed without increased perioperative risk if CAS is performed in high-volume centers by highly skilled operators.

The Registro Italiano per lo Stenting Carotideo (RISC, Italian Registry for Carotid Stenting) has been organized by Italian specialists from different disciplines directly involved in the prevention of stroke due to carotid plaques through stenting of carotid lesions. The Registry has been endorsed by the national societies of 4 different specialties: vascular surgery, interventional cardiology, radiology, and neuroradiology. Each society contributed in the planning stage.The basis for the registry is to collect data on carotid stenting procedures performed by different specialists with different techniques in a “real-world” setting without the limitations of a randomized clinical trial. The Registry was funded to enroll at least 1200 patients over a minimum period of 36 months. The results will be analyzed using the intention-to-treat principle and are anticipated in late 2006. Primary endpoints of the registry are the 30-day combined death and stroke rate and the occurrence of restenosis and ipsilateral neurological deficit at 12 and 24 months. Considerable attention has been paid to the registry's quality control program to ensure scientific validation. An online database facilitates the collection of data with speed and accuracy.

Purpose: To report a prospective evaluation of the 30-day clinical neurological outcome in patients percutaneously treated for severe symptomatic and asymptomatic soft echolucent carotid plaques under cerebral protection from a proximal flow blockade system.Methods: From December 2001 to February 2005, 84 consecutive patients (63 men; mean age 70.7±7.1 years, range 58–81) with documented soft echolucent (gray scale median <25) extracranial carotid lesions were enrolled in a study of percutaneous stenting under cerebral protection achieved by a proximal endovascular clamping device. Primary end-point of the study was the all stroke and death rate at 30 days. Secondary endpoints were angiographic success and any complication between discharge and 30 days. All adverse events were analyzed by an independent neurological team.Results: Total neurological events at 30-day follow-up included 3 transient ischemic attacks and 1 minor stroke (4.8% neurological event rate). The 30-day rates of stroke and neurological death/stroke were both 1.2%; the all death/stroke rate was 2.4%. Clamping intolerance was observed in 5.9% of cases, but there was no interruption in the procedure or clinical sequelae. In 66.7% of patients, visible debris was collected during the procedure.Conclusion: Protected CAS with proximal flow blockage can successfully be applied in selected patients for soft carotid plaques at high risk for intraprocedural embolic events.

Purpose: To evaluate the feasibility of cerebral protection during carotid artery stenting (CAS) using the Mo.Ma device, which prevents cerebral embolization by proximal endovascular blockage of blood flow in the internal and external carotid arteries.Methods: In 14 European centers, 157 patients (121 men; mean age 68.0±8.3 years) were enrolled in a prospective registry between March 2002 and March 2003. Eligible patients had a symptomatic (>50%) or asymptomatic (>70%) stenosis of the internal carotid artery suitable for carotid stenting. Protected carotid stenting was performed with the Mo.Ma system, which occludes both the common and external carotid arteries via 2 independently inflatable compliant low-pressure balloons before any device is advanced across the lesion. Blood is aspirated through the catheter intermittently or at the end of the procedure.Results: The device was successfully positioned and stents were implanted in all cases. Diameter stenosis was reduced from 84.1%±7.8% to 6.7%±5.1%. The mean duration of flow blockage was 7.6±5.9 minutes. In 12 (7.6%) patients, transient intolerance to flow blockade was observed, but the procedures were completed successfully. In 124 (79.6%) cases, there was macroscopic evidence of debris after filtering the aspirated blood. In-hospital complications included 4 (2.5%) minor strokes, 8 (5.1%) transient ischemic attacks, no deaths, and no major strokes, resulting in a 2.5% death/stroke rate at discharge. At 30-day follow-up, there was 1 cardiac death, 1 major stroke, and 3 minor strokes, for an overall 5.7% 30-day death/stroke rate and a 30-day major stroke and death rate of 1.3%.Conclusions: Cerebral protection with proximal endovascular blood flow blockage during CAS is feasible, with a high procedural success rate.

Purpose: To report a retrospective study that sought to identify clinical factors contributing to the development of in-stent restenosis in the carotid arteries, to profile the patients at greatest risk, and to review the treatment modalities evolved from our experience.Methods: Between December 2000 and April 2003, 195 carotid angioplasty/stenting (CAS) procedures (12 bilateral) were performed in 183 patients (131 men; median age 65.9 years, interquartile range 55.2–72.7). Stenting for de novo stenoses was performed in 119 (61%) carotid arteries; 76 (39%) vessels were treated for postsurgical restenosis. Nearly two thirds of the patients (117, 64%) were symptomatic. Patients were evaluated at 3 and 6 months and at 6-month intervals thereafter with duplex ultrasonography. Angiography was used to confirm any recurrent lesion detected on the ultrasound scan.Results: Overall perioperative neurological complications included 4 (2.2%) minor strokes, 1 (0.5%) intracranial hemorrhage, and 1 (0.5%) major stroke; both patients with major neurological complications died at 5 and 12 days, respectively, after the procedure. During the 12.5-month follow-up (range 0–27.2), 3 non-procedure-related late deaths and another 9 (4.9%) neurological events occurred (2 strokes and 7 transient ischemic attacks). In-stent restenosis after CAS was present in 10 (5.2%) of 193 carotid arteries (9/181 patients) in follow-up; all but 1 artery had been treated for postsurgical restenosis. All lesions were treated secondarily with endovascular procedures. Statistical analysis demonstrated that postsurgical restenosis was the only predictive factor for the development of in-stent restenosis (OR 15.5, 95% CI 2.05 to 125.6, p = 0.001) in this cohort.Conclusions: The present study, far from being exhaustive on the subject, indicates that patients who develop restenosis after carotid endarterectomy are also prone to develop restenosis after CAS; moreover, although strongly recommended for postsurgical restenosis, CAS carries a greater risk of in-stent restenosis in this subgroup, thus reducing the benefits of this procedure.

Purpose: To evaluate the impact of cerebral protection devices on the procedural safety and outcome of carotid stent procedures.Methods: From June 1997 to July 2001, 275 consecutive patients (208 men; mean age 71 ± 7.4 years) underwent percutaneous angioplasty and/or stenting of the extracranial carotid artery. In the first 125 (45.4%) patients, the procedures were performed without cerebral protection. After January 2000, protection devices were routinely used (150 [54.6%] patients), including the Angioguard filter, GuardWire occlusion system, TRAP Vascular Filtration System, EPI Filter Wire, NeuroShield, Parodi Anti-Embolism System, and Medicorp occlusive balloon.Results: The percutaneous procedures were effective in 273 (99.3%) patients. No death or major stroke occurred in either group. In the unprotected group, 5 (4.0%) complications occurred: 3 (2.4%) minor strokes, 1 (0.8%) transient ischemic attack (TIA), and 1 (0.8%) subarachnoid hemorrhage. In the patients treated under cerebral protection, there were 2 (1.3%) complications: 1 (0.7%) minor stroke and 1 (0.7%) subarachnoid hemorrhage. There were 4 (3.2%) periprocedural embolic complications in the unprotected group versus 1 (0.7%) in the protected patients.Conclusions: Our data suggest that percutaneous dilation and stenting of the carotid arteries protected by cerebral protection devices is feasible and effective. In a consecutive series, the use of the cerebral protection systems reduced the acute neurological event rate related to embolic complications by 79%.

Purpose: To evaluate the feasibility, safety, and efficacy of the TRAP Vascular Filtration System (VFS) during carotid interventions as a deterrent to embolic complications.Methods: Thirty-one consecutive patients (18 men; mean age 72 ± 8 years) gave informed consent to undergo elective percutaneous angioplasty and stenting of the extracranial carotid artery protected by the TRAP VFS, a nitinol basket filter system.Results: The TRAP VFS was delivered and retrieved safely in all patients; procedural success for carotid stenting was 100%. In 3 (9.7%) cases, the filters were positioned after lesion predilation. Nearly half (13, 41.9%) of the retrieved filters contained visible plaque debris that histology identified as cholesterol crystals, fibrin material, atheromatous plaque, and macrophage foam cells. There were no symptomatic major or minor neurological complications encountered in this cohort during hospitalization.Conclusions: Our data indicate that percutaneous dilation and stenting of the carotid artery protected by TRAP VFS appears to be feasible, safe, and effective in preventing cerebral embolization.

Abstract. The NIR stent is an expandable cellular coronary prosthesis with high flexibility and excellent trackability. The very low crossing profile, associated to the high flexibility, makes this stent suitable for complex and distal lesions. The aim of this study was to evaluate the feasibility, safety, and long-term (clinical follow-up) efficacy of elective and/or urgent deployment of the NIR stent in a broad patient group with coronary artery disease. Between June 1996 and May 1997, 986 NIR stents were implanted in 781 vessels (de novo or restenotic lesions in native vessels, saphenous vein grafts and internal mammary conduits) of 709 consecutive patients (498 men, 211 women) undergoing coronary angioplasty in two Villa Maria Group Catheterization Laboratories. Procedural angiographic success was achieved in 98.4% of all the lesions treated, ranging from 100% success rate in type A lesion to 97.6% in type C lesions (overall procedural success, 98.4%). Major adverse cardiac events (MACE) were considered from PTCA/stenting time to the patient discharge. The in-hospital MACE were limited and occurred in 15 patients: urgent surgical revascularization 0.8%, death 0.7%, sub-acute stent thrombosis 0.5% (overall in-hospital MACE rate 2.1%). Clinical follow-up data were obtained at 8.6 ± 2.8 months following the stenting procedure. The event-free survival rate was 87.9%. The late MACE rate evaluation showed death, target lesion revascularization 9.9% (over-all late MACE rate 12.1%). The NIR stent performances in this broad patient population were excellent, showing very high procedural success rate both in normal and complex coronary anatomy. On the basis of the previous data, we can define NIR stent a safe multifunctional device suitable both for easy and complex situations. The clinical late results are very promising in term of event-free survivals and late MACE.

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For more than 50 years, carotid endarterectomy has been considered the gold standard therapy to prevent stroke in patients with carotid artery disease. Carotid artery stenting (CAS) has emerged in the last 15 years as minimally invasive alternative to surgery, especially in patients at high surgical risk. Recent randomized trials have challenged this concept reporting a relatively high incidence rate (4–6%) of post-CAS neurological adverse events. The aim of this study is to evaluate the current role of CAS in all-comers with advanced carotid disease, managed with mandatory proximal neuroprotection in a high-volume centre. From our database, the last 393 consecutive patients, from January 2011 to August 2013, undergoing CAS under proximal neuroprotection were analysed (mean age 72 ± 8 years). Indications included symptomatic stenoses =60% (n = 87; 22%) and asymptomatic stenoses =80% (n = 306; 78%). In an intention-to-treat approach, CAS success rate was 100%. The in-hospital all stroke/death rate was 1% (minor stroke 1%, major stroke 0%, and death 0%), and the rate of myocardial infarction was 0.3%. The minor stroke rate was 2.3% in symptomatic patients and 0.7% in asymptomatic patients. Carotid artery stenting performed in a high experience centre with the use of proximal embolic protection device is safe and has a low incidence rate of stroke.

The best therapeutic strategy for patients with concomitant carotid obstructive disease (COD) and coronary artery disease (CAD) remains controversial. The aim of the study is to observe post-procedural and 1-year clinical outcomes of patients with COD and CAD after an endovascular, surgical, or a combined (hybrid) revascularization approach, selected by consensus of a multidisciplinary team. Between January 2006 and December 2012, 1043 consecutive patients with COD and concomitant CAD were treated. According to treatment strategies, patients were divided into three groups: surgical: 391 patients (37.1%), endovascular: 502 (48.1%), and hybrid (combined surgical and percutaneous revascularization): 129 (12.4%). The remaining 21 patients were managed medically only and not analysed. The primary end point of the study was a composite of death, myocardial infarction (MI), and stroke at 1-year follow-up; secondary end points included a composite of death, MI, and stroke in-hospital, and major bleeding complications. In hospital, mortality was higher in the surgical group (2.3 vs. 0.2 and 0%, P < 0.001), more strokes occurred in the endovascular group (2.0 vs. 0.5 and 0.8%, P = 0.03), and major bleedings were more frequent among hybrid patients (13.9 vs. 3.8 and 5.5%, P = 0.001). The incidence rate of the primary end point (hierarchical at 1 year) occurred in 6.0% of the study population (5.8, 6.5, and 4.6%, respectively; P = ns for all groups). Surgical and endovascular treatments yield remarkable clinical results both at acute and 1-year follow-up. The best-suited revascularization strategy should be discussed in a multidisciplinary context, and chosen according to the clinical characteristics of each single case and local expertise.

Antiplatelet therapy is the cornerstone of the pharmacologic management of patients with acute coronary syndrome (ACS). Over the last years, several studies have evaluated old and new oral or intravenous antiplatelet agents in ACS patients. In particular, research was focused on assessing superiority of two novel platelet adenosine diphosphate (ADP) P2Y12 receptor antagonists (i.e. prasugrel and ticagrelor) over clopidogrel. Several large randomized controlled trials have been undertaken in this setting and a wide variety of pre-specified and post hoc analyses are available that evaluated the potential benefits of novel antiplatelet therapies in different subsets of patients with ACS. The aim of this document is to review recent data on the use of current antiplatelet agents for in-hospital treatment of ACS patients. For each drug or class of drugs, strong evidence and/or areas of uncertainty that warrant further research are highlighted by examining 10 subgroups of patients with ACS.